Abstract

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

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Footnotes

Contributors JIS and JSB are joint first authors. JIS, JSB and GCD conceived the idea for this review article. JIS and JSB carried out a review of literature as outlined in text and put together the figures. JIS, JSB and GCD together interpreted the literature and wrote the manuscript. All authors gave final approval for the submitted article and take responsibility for the accuracy and integrity of this work.

Competing interests GCD is supported by the NIHR Biomedical Research Centre (BRC), Oxford and has research funding from the Oxford BRC, MRC(UK) and Merck Serono. GCD has received travel expenses from Bay Schering, Biogen Idec, Genzyme, Merck Serono and Novartis, and honoraria as an invited speaker for Bayer Schering and Novartis.

Provenance and peer review Commissioned; externally peer reviewed.

Correction notice This article has been corrected sine it was published Online First. The Contributorship statement has been updated.

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